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CAPSULESFilms & Foils
MACHINESINSPECTION SYSTEMS
Partnering in Excellence
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Our Vision, Mission and Values
Comprehensive Solution for cDPI:
Opportunities, Trends & Possibilities
Webinar 9th November 2017
Content
• Introduction
• Inhalation Technology
• Capsules Based Inhalers
• Types of Capsules
• Advantages - Case Studies
• Products in the Market / Pipeline
• ACG Holistic solution
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Greek physicians inhalation of volcanic Sulphur vapours
Bennet. First published
Inhaler illustration Chloroform
A. Newton. First DPI patentKaplin. Adrenalin inhaled
R. Altounyan. Spinhaler
D. Jack. Rotahaler/Salbutamol
Spiriva Handihaler approval
Ultibro Breezhaler approvalInhalation milestones
400BC
1654
1846
1864
1911
1963
1969
2004
2016
Research Literature:
Capsules in DPI
• Analysis of papers reporting test results from 1971-2013
Year Number of Papers
1971-1980 6
1981-1990 12
1991-2000 45
2001-2005 47
2006-2010 87
2011-2013 95
Inhalation Technology
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Lung structure
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Alveolar region
• Surface: 140 m2
• Number: 500 millions
• Volume air: 2-6 l.
• Volume blood = 100-200ml
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Comparison of Dosage Forms
Available to Treat Respiratory Diseases
Attribute Oral delivery Inhaled delivery
Total dose ≥ 400 mg daily ≤ 40 mg daily
Lung to plasma
exposure ratioLow High
Bioavailability 55 % (in Itraconazole)≥ 60% directly to site
of administration
Lung exposure Variable, affected by diet Consistently high
Side effects
Systemically & orally
driven:
•Gastrointestinal
•Phototoxicity(Voriconazole)
•Drug-drug interactions
Locally driven
Advantages
Simple
Easy-to-use
Better patient
outcome
Pulmonary route provides consistent drug delivery with high lung deposition
Source: Sermet-Gaudelus et al, Antimicrobial agents Chemotherapy (2001),
Cold Spring Harb Perspect Med (2015)
Inhalation: The Golden Rule
• Particle size does matter. Only particles in
the 1-5 micron range are active
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Particle density
Particle shape
Geometric diameter
Aerodynamic diameter
Why Particle Size is Important?
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From Fischler et al . Particle dynamics (2015)
Indicators
• EMITTED DOSE (µg): TOTAL MASS OF DRUG DEPOSITING IN THE MOUTH PIECE ,
INDUCTION PORT, PRESEPARATOR AND NGI (Next Generation Impactor) STAGES
• FINE PARTICLE DOSE (µg): MASS OF DRUG DEPOSITED IN THE NGI WITH
AERODYNAMIC DIAMETERS <4.46µM
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Dry Powder Inhalation (DPI)
▪ Transforms liquid medication into aerosol
▪ Requires coordination between the actuation of device and inhalation
Nebulizers
MDI
▪ Formulated in solution or suspension using a liquid propellant
▪ Requires coordination between the actuation of device and inhalation
cDPI is an optimal solution for drug delivery because of recent particle engineering
▪ Drug is inhaled by inspiratory mechanism
▪ The powder formulation does not require use of propellant
Blister based
Dry Powder Inhaler
Reservoir based
Dry Powder Inhaler
Capsule based
Dry Powder Inhaler
Types of DPIs
DPI Formulation Design
Use of Excipients in Pulmonary Drug Delivery
EXCIPIENTS DESCRIPTION COMMENTS
Sugars: Lactose,
Mannitol, Glucose
Coarse fine carrier Approved and
commonly used
Hydrophobic additives:
Mg stearate
Protection for drug
moisture
Approved
Amino acids: Leucine,
Trileucine
Improved aerosol
efficiency
Endogenous substance
but no data on lung
toxicity
Surfactants: Poloxamer.
Bile salts
Production of light and
porous particles
Accepted at low dose
Biodegradable
polymers:
PLGA
Used in sustained
release formulation
Immunogenicity effect
observed
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From Seebri Neohaler guide
Capsule Based Inhalers
Mechanism of Action
• Puncturing: opening of capsule.
• Aerosolization: after inspiration, drug is
released to the lung.
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POSITIONS OF OPENINGS
Source “Powder Capsule and Device”. Aurelie Schouben et al. IJP 2015
Capsule Puncturing (1/2)
Capsule Puncturing (2/2)
0
0.5
1
1.5
2
2.5
3
3.5
0 0.5 1 1.5 2 2.5 3 3.5
Fo
rce
(N)
Deformation (mm)
Force / Deformation for Hard Capsules
(1) (2)
(3)
Torrisi et al. IJP 2013
Source “Pierce and Inhale”. F. Martinelli et al
Capsule Spinning
• At 60 l/m the capsule’s
angular velocity can reach
2800 rpm
• The low moment of inertia
of the capsule makes
possible such high values
• The forces generated at
this rotation deagglomerate
the mixture
Computational Fluid Dynamics
Source “Use of computational modelling” Zhou et al
Agglomerates Dispersed by Drag Force
Redrawn from Kou et al. Powder dispersion mechanism. IJP (2016)
CAPSULE TYPES
Gelatin
GelatinPEG
HPMC
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GELATIN GELATIN-PEG HPMC
ORIGIN ANIMAL ANIMAL VEGETABLE
STRUCTURE PROTEIN PROTEIN CELLULOSE
MOISTURE
CONTENT (%)
13 - 16 10 - 12 3 - 8
BRITTLENESS AT
LOW RH
Yes Medium Very low
CROSSLINKING Yes Yes No
Ezeeflo™ Capsule Properties
Puncturing
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From Birchall et al. Drug delivery Pharm 2009
Puncturing: 40 Total with 1 Cyclohaler
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0
20
40
60
80
100
Gelatin A ACG Gelatin ACG HPMC
% G
OO
D C
AP
SU
LE
S
TYPE OF CAPSULE
% GOOD CAPSULES @ 75% RH / 20ºC
From J. Kalafat et al. Inhalation delivery Using DOE to optimize puncturing AAPS 2017
Puncturing: 40 Total with 2 Cyclohalers (20+20)
0
20
40
60
80
100
Gelatin A ACG Gelatin ACG HPMC
% G
OO
D C
AP
SU
LE
S
TYPE OF CAPSULE
% GOOD CAPSULES @ 75% RH / 25ºC
From J. Kalafat et al. Inhalation delivery. Using DOE to optimize puncturing. AAPS 2017
Aerosolization
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Lactose +salbutamol
Gelatin
HPMC
60L/m 4s
From Saleem et al. “Comparison of two different types of inhalation capsules AAPS 2012
Aerosolization
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From Saleem et al. “Comparison of two different types of inhalation capsules AAPS 2012
Capillary Condensation
Case Studies: Advantages
• High drug doses products
• Moisture sensitive products
• Amorphous powders
• Reproducibility
• Cost
• Environmental
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High Dose Drugs
• Pulmonary delivery can achieve a superior therapeutic effect
at a fraction of the systemic dose.
• Oral dose of 2-4 mg Salbutamol is therapeutically equivalent
to 100-200 ug by inhalation
• Diseases as cystic fibrosis and lung infections require high
drug concentrations in lung.
• High intravenous doses may carry systemic toxicity
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From Labiris & Dolovich: Pulmonary Drug Delivery. Part I. Physiological factors affecting therapeutic effectiveness of aerosolized medications
High Dose Drugs
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1 mg 10 mg 100 mg 1000 mg
MDI DPI cDPI Nebulizer
Lung Dosage
High Dose Drugs
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Colobreath Turbospin. Lung infections. Forest Laboratories. Gelatin capsule 125mg
High Dose Drugs
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Moisture Sensitive Drugs
• Most of the inhaled drugs are moisture sensitive
• In order to avoid drug degradation it is convenient that the
container has low moisture content
• The HPMC capsules moisture content can be reduced at
very low values storing the capsule at the convenient
relative humidity
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Correlation RH / HPMC Capsule Moisture Content
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y = 0.7832e0.0367x
R² = 0.974
0
2
4
6
8
10
12
14
16
0 10 20 30 40 50 60 70 80 90
Ca
psu
le m
ois
ture
co
nte
nt(%
)
RH (%)
HPMC Capsule Moisture Content vs Relative Humidity
Moisture Sensitive Drugs
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EMPTY CAPSULES
(3 - 8%)
CAPSULES FILLING
STORING CAPSULES AT
LOW RELATIVE HUMIDITY
PACKAGING AND
BLISTERING
Moisture Sensitive Products
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 2 4 6 8 16
TIP (Tobramycin in powder)
TIS (Tobramycin in solution)
10 12 14Source: Newhouse et al. Chest 2003
cDPI delivers effective, evidence based dosage outcome
Time (h)
Ug/ml
Amorphous Powders
• Some inhalation drugs are more effective in amorphous state
• Amorphous solids are unstable and can undergo crystallization
• HPMC capsules are a good solution to the problem
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Amorphous Powders
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Braltus. Amorphous Tiotropium in HPMC
capsules. 22 ug of Spiriva are
therapeutically equivalent to 14 ug of
Braltus
Reproducibility
• Formoterol delivered in different platforms
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Foradil cDPI Gelatin Formagal. cDPI HPMC DPI DPI MDI
Reproducibility: Formoterol in DPI
Source: “Marketed Formoterol inhalation aerosols” Wauthoz et al. RDD 2015
cDPI (gel) cDPI (HPMC) DPI DPI MDI
Cost
• Device costs are mainly originated by the number of high
precision parts needed and the assembly costs
• Reservoir based and blister based DPI devices normally
require more then 20 plastic and metal parts
• Capsule based systems are composed between
6-10 parts including needles
• It is easier filling a capsule than a blister or reservoir
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Capsule based Blister based
Environmental
• MDIs use in the formulation propellants.
• The Montreal protocol ensured a planned phasing out of
CFC. They were replaced by HFC.
• HFCs do not deplete the ozone layer but they are
powerful greenhouse gases. They have a global warming
effect of up to 3800 times that the carbon dioxide.
• DPIs does not use propellants and have a carbon
footprint 18 times lower than MDI.
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Products in the Market / Pipeline
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cDPI – Commerical Products
Product Capsule Material Company
Onbrez Gelatin Novartis
Foradil Gelatin Novartis
Seebri HPMC Novartis
Ultibro HPMC Novartis
Spiriva Gelatin-PEG Boehringer
Drug product Substance Target Type Company Status
Tobi-Podhaler Tobramycine P.Aeruginosa DPI Novartis Approved (USA only)
Colobreathe Colistin P.Aeruginosa DPI Forest Approved (EU only)
Ciprofloxacin Ciprofloxacin PAeruginosa DPI Bayer Phase 3
Aerovanc Vancomycin MRSA DPI Savara Phase 3
PUR 1900 Itraconazole Aspergillus DPI Pulmatrix Preclinic
CIC/FF/TIO Unknown COPD DPI CIPLA Phase 3
Oxitocine Oxitocine Hormone DPI GSK Phase 2
Levodopa Levodopa Parkinson’s DPI Civitas Phase 2
Unknown Unknown COPD DPI Novartis Phase 3
Unknown Unknown COPD DPI Zambon Phase 3
DPI Products in Pipeline
New Therapies in DPI
Parkinson's
disease
•Inhaled Levodopa for the treatment of Parkinson’s
disease
•ARCUS inhaler allows delivery of 10 mg of drug in a
single inhalation
Migraine•Inhaled Sumatriptan (nasal delivery) is used in
treatment of acute migraine
Ezeeflo™
Capsules
ACG’s Holistic DPI
Solution
DPI capsule
filling machine
Formulation
expertise
Packaging
solutions
ACG’s Holistic DPI Solution
ACG Capsules : Global Footprint
Subsidiaries: Argentina, Bangladesh,
Brazil, Canada, China, Croatia,
Indonesia, Thailand, UAE, UK, USA
Manufacturing: Brazil*, Europe, India
Global Head Office: India
Warehouses: Argentina, Brazil, Europe,
Indonesia, Thailand, USA
*Manufacturing plant under construction
Co. Sales Manager: Colombia,
Germany, France, Spain
Evolution of ACG
From a small beginning in 1961 in India, ACG Worldwide has established as a leading global player and continues to grow
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19611972
1987
1993
1996
2009
2010
ACG-ACPLEmpty Hard Capsules
ACG-PAMPharma Machines
ACG-PAMPACPackaging Machines
ACG-PHARMAPACPackaging/ Barrier Films
ACG-PHARMATECHProcess Equipment
ACG-INSPECTIONVisual Inspection Systems
ACG-VALUE LINKSHitech Machinery
Agency
Explore What Can We Achieve Together
We believe that our responsibility does not end by supplying the capsules as per
specifications, it begins there. With strive to add tangible value to our
strategic key customers and create a win-win partnership with them
ACG - Values
VALUES WE LIVE.. VALUES THAT MAKES US ACG..
Transparent Aesthetics Nurturing Safety
Synergy Customer Centric Empowerment Dignity